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许多 si/shRNAs 通过一种非靶向机制针对多个存活基因来杀死癌细胞。

Many si/shRNAs can kill cancer cells by targeting multiple survival genes through an off-target mechanism.

机构信息

Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, United States.

European Bioinformatics Institute (EMBL-EBI), Cambridge, United Kingdom.

出版信息

Elife. 2017 Oct 24;6:e29702. doi: 10.7554/eLife.29702.

DOI:10.7554/eLife.29702
PMID:29063830
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5655136/
Abstract

Over 80% of multiple-tested siRNAs and shRNAs targeting CD95 or CD95 ligand (CD95L) induce a form of cell death characterized by simultaneous activation of multiple cell death pathways preferentially killing transformed and cancer stem cells. We now show these si/shRNAs kill cancer cells through canonical RNAi by targeting the 3'UTR of critical survival genes in a unique form of off-target effect we call DISE (death induced by survival gene elimination). Drosha and Dicer-deficient cells, devoid of most miRNAs, are hypersensitive to DISE, suggesting cellular miRNAs protect cells from this form of cell death. By testing 4666 shRNAs derived from the CD95 and CD95L mRNA sequences and an unrelated control gene, Venus, we have identified many toxic sequences - most of them located in the open reading frame of CD95L. We propose that specific toxic RNAi-active sequences present in the genome can kill cancer cells.

摘要

超过 80%的靶向 CD95 或 CD95 配体（CD95L）的多重测试 siRNA 和 shRNA 诱导一种细胞死亡形式，其特征是同时激活多种细胞死亡途径，优先杀死转化和癌症干细胞。我们现在通过靶向关键生存基因的 3'UTR 来证明这些 si/shRNAs 通过经典 RNAi 杀死癌细胞，这是一种我们称为 DISE（通过生存基因消除诱导的死亡）的独特的脱靶效应。缺乏 Drosha 和 Dicer 的细胞，缺乏大多数 miRNAs，对 DISE 高度敏感，表明细胞 miRNAs 保护细胞免受这种形式的细胞死亡。通过测试源自 CD95 和 CD95L mRNA 序列和一个不相关的对照基因 Venus 的 4666 个 shRNA，我们已经鉴定出许多毒性序列 - 大多数位于 CD95L 的开放阅读框中。我们提出，基因组中存在的特定毒性 RNAi 活性序列可以杀死癌细胞。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/310b/5655136/8568992d9799/elife-29702-fig7-figsupp1.jpg
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